1. Field of the Invention
The present invention relates generally to the field of drug delivery and more particularly to apparatus and methods for the enhanced transdermal and localized internal delivery of drugs to patients.
Drug therapy is the treatment of choice for many diseases and conditions. Drugs may be administered to the patients in a variety of ways, including systemic delivery and localized delivery. Systemic delivery generally requires that the drug enter vascular circulation and may be achieved by conventional techniques, such as injection, oral administration, inhalation, transdermal administration, and the like.
Of particular interest in the present invention, transdermal delivery requires that the drug be systemically absorbed across the patient's skin, usually for an extended period of time. Typically, the drug is incorporated in a matrix or reservoir from which it is released on to the skin. The rate of absorption through the skin can enhanced in several ways, including chemical enhancers, iontophoresis (the application of an external electric field to enhance passage of an ionized drug form across the skin barrier), and phonophoresis (also known as sonophoresis). Of particular interest to the present invention, phonophoresis relies on the application of ultrasonic energy to the drug and/or skin in the region where the drug is being transdermally delivered.
Localized drug delivery can also take a variety of forms. For example, tumors and other localized conditions can be treated by implantation of a drug reservoir or delivery catheter near the diseased site. Intralumenal drug delivery can be effected using catheters having lumens for delivering the drug from an external source to a site of interest. Intralumenal drug delivery has frequently been proposed for the treatment of vascular stenoses and other disease conditions. Enhancement of localized drug delivery from both implants and catheters may be achieved by generally the same methods discussed above in connection with transdermal delivery, i.e. chemical penetration enhancers, iontophoresis, and phonophoresis.
For both transdermal and localized drug delivery, phonophoresis is usually achieved using a piezoelectric ultrasonic transducer which is mechanically or otherwise coupled to the drug or drug delivery device. It is believed that ultrasonic energy enhances the permeability of the outer skin (epidermis) in the case of transdermal delivery, and the tissue or membranes surrounding implants and catheters in the case of localized internal drug delivery. Although the theory of such enhancement is not completely understood, the use of ultrasonic energy for enhancing drug delivery has been quite successful, particularly when employed with proteins, carbohydrates, and other large molecule drugs.
Despite its success, phonophoretic enhancement of drug delivery using piezoelectric ultrasonic transducers suffers from certain drawbacks. For example, piezoelectric ultrasonic transducers generally operate only on a single primary frequency, thus limiting the ability to change the frequency for different applications or change the frequency during the course of a single procedure with a particular patient. Thus, it would be desirable to provide phonophoretic drug delivery systems which allow the frequency to be changed for different uses or during single procedures. Piezoelectric ultrasonic transducers are also relatively inefficient, which can result in excessive power consumption from the batteries used in the systems. Thus, it would be desirable to provide phonophoretic drug delivery systems incorporating ultrasonic or other transducers which can use energy more efficiently than piezoelectric transducers. Additionally, piezoelectric transducers require relatively high voltages for excitation. Thus, it would be desirable to provide phonophoretic systems employing ultrasonic transducers which can operate more efficiently and at lower excitation voltages.
For these reasons, it would be desirable to provide improved phonophoretic drug delivery systems employing transducers meeting at least some of the objectives set forth above. It would be further desirable to provide such systems which can be utilized for both systemic and localized drug delivery, including transdermal delivery, intralumenal delivery, and delivery to internal tissue locations. It would be still further desirable to provide such phonophoretic systems which are low cost, which may be provided as either disposable or reusable (i.e. sterlizable) components. Such apparatus and methods should further be useful as entirely external systems, i.e. with all components located outside the patient's skin, as combined external/internal systems where the power and control component(s) are located externally and the drug delivery component(s) may be transcutaneously implanted or percutaneously delivered to body lumens, or as entirely internal systems where the apparatus may be fully implanted.
2. Description of the Background Art
The use of ultrasonic energy to enhance transdermal drug delivery is described in U.S. Pat. Nos. 5,405,614; 5,323,769; and 5,267,985. The '614 patent notes that sound pulse waves can be produced by transducers which use a coil of wire, but teaches that piezoelectric devices are to be used in transdermal systems. Catheters having ultrasonic enhancement for intralumenal and transcutaneous drug delivery are described in U.S. Pat. Nos. 5,362,309, 5,318,014; 5,315,998; 5,286,254; 5,282,785; 5,269,291; and 5,197,946. Medical publications discussing sonophoresis, phonophoresis, iontophoresis, and related subjects include Pratzel et al. (1986) J. Rheumatol. 13:1122-1125; Burnette, in Developmental Issues and Research Initiatives, Hadcraft and Guy, eds., pages 247-288, Marcel Dekker, Inc., New York, (1989); Benson et al. (1989) Phys. Ther. 69:113-118; Bommannan et al. (1992) Pharm. Res. 9:559-564; Elias, in Percutaneous Absorption, Bronaugh and Maibach, eds. pages 3-12, Marcel Dekker, Inc., New York (1989); Bommannan et al. (1992) Pharm. Res. 9:1043-1047; Menon et al. (1994) Skin Pharmacol. 7: 130-139; and Mitragotri et al. (1995) J. Pharm. Sci. 84:697-706.
Copending applications assigned to the assignee of the present application which describe the type of floating mass transducer employed in the present device include U.S. application Ser. No. 08/680,578, filed Jul. 12, 1996; U.S. application Ser. No. 08/582,301, filed Jan. 3, 1996; U.S. application Ser. No. 08/568;006, filed Dec. 6, 1995; U.S application Ser. No. 08/526,129; filed Sep. 7, 1995; U.S. application Ser. No. 08/368,219; filed Jan. 3, 1995 now U.S. Pat. No. 5,624,376; U.S. application Ser. No. 08/225,153, filed Apr. 8, 1994, now U.S. Pat. No. 5,554,096; and U.S. application Ser. No. 08/087,618, filed Jul. 1, 1993, now U.S. Pat. No. 5,456,654.
The full disclosures of each of the above-listed U.S. patents and copending applications are hereby incorporated herein by reference.